A Proof-Of-Concept Trial of HELIOX with Different Fractions of Helium in a Human Study Modeling Upper Airway Obstruction

European Journal of Applied Physiology (2019) 119:1253–1260 https://doi.org/10.1007/s00421-019-04116-7

ORIGINAL ARTICLE

A proof-of-concept trial of HELIOX with different fractions of helium in a human study modeling upper airway obstruction

Hubert Truebel1,2,6,7 · Sandra Wuester3,7 · Philip Boehme6,7 · Hinnerk Doll7 · Sven Schmiedl4,5,7 · Jacek Szymanski4,5,7,9 · Thorsten Langer1,2,7,8 · Thomas Ostermann7 · Dirk Cysarz7 · Petra Thuermann4,5,7

Received: 26 February 2018 / Accepted: 28 February 2019 / Published online: 8 March 2019 © Springer-Verlag GmbH Germany, part of Springer Nature 2019

Abstract Background Helium in oxygen (HELIOX) can relieve airway obstruction and lower the work of breathing because it increases the threshold at which turbulent gas flow is induced. Less turbulent and more laminar flow lowers the work of breathing. According to guidelines, the fraction of Helium in HELIOX should be maximized (e.g. to 79%). Here, we investigate whether HELIOX with less than 60% of Helium is able to relieve the sensation of dyspnea in healthy volunteers. Methods 44 volunteers underwent resistive loading breathing different gases (medical air and HELIOX with a fraction of 25%, 50% or 75% helium in oxygen) in a double-blinded crossover design. Subjects rated their degree of dyspnea (primary outcome parameter) and the variability of noninvasively measured systolic blood pressure was assessed. Results Dyspnea was significantly reduced by HELIOX-containing mixtures with a fraction of helium of 25% or more. Similarly, blood pressure variability was reduced significantly even with helium 25% during respiratory loading with the higher load, whereas with the smaller load an effect could only be obtained with the highest helium fraction of 75%. Conclusion In this clinical trial, HELIOX with less than 60% of helium in oxygen decreased the sensation of dyspnea and blood pressure variability, a surrogate parameter for airway obstruction. Therefore, higher oxygen fractions might be applied without losing the helium-related benefits for the treatment of upper airway obstruction. Trial registration Registration with clinical trials (NCT00788788) and EMA (EudraCT number: 2006-005289-37).

Keywords Upper airway obstruction · HELIOX · Work of breathing · Clinical proof-of-concept study

Abbreviations ECG Electrocardiography BfArM Bundesinstitut für Arzneimittel und FiHe Fraction of inspired helium Medizinprodukte FiO2 Fraction of inspired oxygen CRP C-reactive protein He Helium ID Inner diameter IRB Institutional Review Board Communicated by Carsten Lundby.

* Hubert Truebel 6 Cardiovascular Research, Bayer Pharma AG, Apratherweg [email protected] 18, 42096 Wuppertal, Germany 7 School of Medicine, Faculty of Health, Witten/Herdecke 1 Department of Pediatrics, HELIOS Clinic Wuppertal, University, Witten, Germany Wuppertal, Germany 8 Department of Neuropediatrics and Muscle Disorders, Center 2 Department of Pediatrics, School of Medicine, Faculty for Pediatrics, Faculty of Medicine, University of Freiburg, of Health, Witten/Herdecke University, Witten, Germany Freiburg, Germany 3 Department of Pediatrics, HELIOS Clinic Schwelm, 9 Medical Center City Region Aachen GmbH, Aachen, Schwelm, Germany Germany 4 Philipp Klee‑Institute for Clinical Pharmacology, HELIOS Clinic Wuppertal, Wuppertal, Germany 5 Department of Clinical Pharmacology, School of Medicine, Faculty of Health, Witten/Herdecke University, Witten, Germany

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MA Medical air physicians and respiratory therapists now have the option to POC Proof of concept titrate inspired helium concentration (FiHe) to the needs of sBP Systolic blood pressure the individual patient to obtain maximum effect of helium STAI State-Trait-Angst-Inventar with adequate oxygenation with the resulting FiO 2 ranging from 21 to 99% in spontaneously breathing subjects (Venka- taraman 2006; McGarvey and Pollack 2008; Truebel 2008). Introduction In most study protocols on the use of HELIOX in upper and lower airway obstruction, investigators used fractions Helium is a nontoxic, tasteless and odorless gas with a low of inhaled Helium between 60 and 80%, i.e. trying to keep solubility in tissue (Hess et al. 2006). The medical use of the FiHe above 60% to maximize helium-associated effects helium is based on its ability to increase the threshold at (Allan et al. 2009; Chiappa et al. 2009; Diehl et al. 2003; which turbulent gas flow in the airway is occurring: in fluid Cambonie et al. 2006; Jolliet et al. 2003; Laveneziana et al. mechanics the Reynolds number (Re), named after Osborne 2011; Colnaghi et al. 2012; Scorsone et al. 2010; Vogiatzis Reynolds (1842–1912) is a dimensionless quantity. It is cal- et al. 2011; Vorwerk and Coats 2010; Ho et al. 2002). Our culated as Re = ρ × u × L/µ with ρ reflecting density of the study addressed the question, whether HELIOX with a FiHe flowing fluid, u being the fluid velocity, L being the length below 60% is effective in reducing sensation of dyspnea dur- of the flow pattern andµ being the dynamic viscosity of the ing a controlled respiratory loading experiment. fluid. In the example at hand, principles from fluid mechanics are used to describe gas flow pattern in the airway to help predict flow patterns in different flow situations. At low Methods Reynolds numbers, flows tend to be dominated by laminar flow and at high Reynolds number turbulence results. Tur- The study was approved by the responsible institutional bulent flow is characterized by chaotic changes in pressure review board (University of Witten protocol-No.: 88/2006) and flow velocity. In contrast in laminar flow regime fluid and the German regulatory agency responsible for clinical flows in organized laminar patterns. In essence less turbu- trials with investigational drugs (Bundesinstitut für Arznei- lent and more laminar flow lowers work of breathing. If one mittel und Medizinprodukte (BfArM; http://www.bfarm takes a look at the definition of the Reynolds number above, .de/), registration code 4032794-3_1_6 as well as clinical- a reduction of the density ρ in the denominator of the equa- trials.gov (registration code NCT 00788788). The trial fol- tion lowers Re thereby increasing the chances of a laminar lowed a randomized, double-blind, intra-individual, sixfold flow pattern which is why the admixture of helium could crossover design. The study was carried out in accordance to lower work of breathing (see also Truebel 2008). Helium the declaration of Helsinki (http://www.wma.net/en/30pub in combination with oxygen (HELIOX) was first used by lications/10policies/b3/). Barach in New York for the treatment of asthma and upper airway obstruction in 1934 (AL 1934, 1935). In the clinical Study sequence setting, the inhaled gas mixture HELIOX usually consists of helium with a variable oxygen content of at least 21% Study subjects received written information about the study up to a fractional inspired oxygen concentration (FiO 2) of via mail and those willing to participate came to the study 100% which would no longer be considered HELIOX. In site in the Helios-Klinikum in Wuppertal/Germany a few some cases, additional admixtures, e.g. nitric oxide (NO) days prior to the study to receive a tour to the site including or other medical gases are added (Harris and Barnes 2008; a health questionnaire and the informed consent form which Hess et al. 2006; McGarvey and Pollack 2008; Siobal 2009). was explained to them. Furthermore, blood and urine tests HELIOX is mainly viewed as a rescue procedure in certain were conducted during this pre-visit as part of the screening conditions affecting the upper and lower airways in which procedure. the gas could be delivered via nasal cannula, face mask On the day of the study, the participants could again ask or endotracheal tube from a gas tank at the bedside or via questions, were examined and had to provide the signed con- specifically equipped ventilators (Haynes2006 ; McGarvey sent form. When the participants were disease free, labora- and Pollack 2008; Lazarus 2010; Truebel 2008; Beurskens tory values were within normal limits and in female partici- et al. 2014; Haussermann et al. 2015; Long et al. 2016; Liet pants the urine pregnancy test was negative, they proceeded et al. 2015). In general, diseases affecting the (upper) airway to draw from a stack of closed envelopes. This way the order resistance seem to be more amenable to the application of of treatments was randomized. In the envelope, a detailed HELIOX than conditions that affect the pulmonary paren- instruction provided information to the participants on which chyma (McGarvey and Pollack 2008; Levy et al. 2016). With room to enter (i.e. pre-study- and treatment-room) and what new ventilators and gas blenders having reached the market, to do upon entering these rooms. It also contained a coded

1 3 European Journal of Applied Physiology (2019) 119:1253–1260 1255 information for the physician that operated the gas mixtures The degree of dyspnea during the experiment was rated (see below; “technical investigator”). Since a second physi- by the subjects on a visual categorical scale ranging from 1 cian (i.e. the “study physician”), that was with the partici- (no feeling of dyspnea) to 10 (maximum feeling of dyspnea) pant during the study measurement and that was taking care according to Borg (1982). of the recording devices, was seated in a separate room from During the study electrocardiogram (ECG) and nonin- the one that mixed the gases, the study was conducted in a vasive systolic blood pressure were monitored (sBP) with double-blind and randomized fashion. the Task Force® Monitor (TFM; CNSystems, Graz, Austria, for details please also see Enneper et al. 2005). Changes Subjects in systolic blood pressure were recorded continuously to detect respiratory effects on sBP-variability (also known as 44 healthy adult male and female volunteers (Table 1) were Pulsus paradoxus) caused by changes in airway resistance enrolled after a written, informed consent had been obtained associated with study interventions (Lee et al. 2005; Gold- previously. For inclusion, questionnaires as well as a physi- man et al. 1995), i.e. the variation of systolic blood pressure cal examination were required to rule out any signs of acute is aggravated during resistive breathing and can be used as or chronic airway disease or cardiac pathology. Furthermore, an indirect measure of upper airway obstruction. Further a laboratory screen including total blood count, creatinine, details on the effect size to judge the sample size as well transaminase profile as well as measurement of C-reactive the amplitude of the effect have been studied in a pre-study protein (CRP) and a fasting blood sugar measurement had beforehand (Enneper et al. 2005). All subjects were studied to reveal normal findings. A negative pregnancy test was in the seated position, with a nose clip in place and a pulse- mandatory for females. oximeter attached to a finger (PVM-2700, Nihon Kohden Subjects were further excluded when signs and symp- Europe GmbH, Rosbach/Germany; where pulse-oximetry toms for mental health problems could be revealed by his- data could not be stored electronically). Each condition was tory taking. Furthermore, prior to the study potential par- recorded for exactly 2 min. Ample time (between 30 and ticipants were screened in respect to their current baseline 45 s) was provided before a recording period of 2 min was anxiety level using of the German version of the STAI-G started to allow for distribution of the tested gas mixture in X1 questionnaire [State-Trait-Anxiety-Inventory (STAI); the subjects’ respiratory tract and thereby achieve steady- Verlag für Psychologie, Goettingen, Germany. Manual for state conditions. the State-Trait Anxiety Inventory. Palo Alto, CA: Consult- After each gas mixture was changed, care was taken ing Psychologists Press]. Volunteers were excluded if their to flush all tubing and the reservoir bag with the next gas anxiety level exceeded a score of 60 according to a study by mixture to be tested. After the subjects were breathing the Osborne et al. (2000). control gas [MA (medical air)] or a helium-containing gas mixture, they marked their degree of dyspnea on the visual Measurements categorical scale mentioned above. In total, the degree of dyspnea was rated 12 times per subject. The total time need Before entering the treatment room, subjects conducted a to carry out the experiment per subject was about 150 min 2-min breathing trial (“pre-study”) through a resistor in a (excluding the initial screening and blood draw). separate room to accustom themselves with the study loca- tion and accommodate to the feeling of dyspnea imposed by Test gases a resistive load. ‘This “pre-study” was added to the experimental protocol because a pilot study revealed some degree A reservoir bag was filled with gas mixed in a separate of adaptation after subjects’ first experience with resistor- room via gas tubing (Fig. 2). The Helontix™Vent (Linde modified breathing (Enneper et al.2005 ). Gas Therapeutics, Unterschleißheim, Germany) in constant

Table 1 Characteristics of the n = 44 included subjects Block 1 (n = 11) SD Block 2 (n = 11) SD Block 3 (n = 11) SD Block 4 (n = 11) SD

Age (years) 26.4 ± 6.7 26.7 ± 6 23.8 ± 1.3 25.0 ± 3.2 BMI (m2/kg) 20.7 ± 1.8 22.7 ± 3 22.5 ± 3.5 22.4 ± 2.3 Pre-study STAI-G 31.8 ± 5.1 33.6 ± 7.3 34.3 ± 10.8 35.8 ± 6.7 Pre-study Borg 4.7 ± 1.7 5.2 ± 1.1 4.2 ± 1 3.8 ± 1.4 Dyspnea Score

Values are mean (SD); definition of abbreviation: BMI body mass index

1 3 1256 European Journal of Applied Physiology (2019) 119:1253–1260 flow mode at a flow rate of 12 l/min was used to mix dif- USA; ID 35 mm). Subjects were breathing from a reservoir ferent fractions of helium. Therefore, gas from containers bag via an inspiratory resistor (tube A or B) and exhaling (BOC Medical, Guildford Surrey, England) filled with 21% into the room via a fixed expiratory resistor which was oxygen and 79% helium was mixed with oxygen (Conoxia™, needed for adequate seal of the three-way respiratory valve Linde Gas Therapeutics) in the Helontix™Vent. Three dif- (see “V” in Fig. 1; Harvard Apparatus, ID 35 mm) which ferent mixtures of helium in oxygen with a helium content directed the gas stream. of 25%, 50% and 75% in oxygen (FiHe 25, FiHe 50 and FiHe 75, respectively) were used. Before each HELIOX-exposure, Medical Air (“MA” in Fig. 1; Linde Gas Therapeutics) was Blinding and randomization protocol used as control condition. Subjects at all times were una- ware of the type of gas mixture. The person operating the By means of block randomization with sixfold intra-indi- Helontix™Vent (“technical investigator”) was not in contact vidual crossover, each subject was randomized to one of with the subject but volunteers were always supervised by a the exposure schedules displayed in Fig. 2. For practical physician (“study physician”). reasons, it was not feasible to consider all 36 permuta- tions of the six combinations of resistors and helium con- Respiratory loading centrations. To exclude large sequence effects, the order of resistors was considered as well as the extreme posi- Two different external resistors (see “R” in Fig. 1) were tions of lowest and highest helium concentrations since used. They were self-made by placing standard plastic we expected some fatigue and a higher degree of dyspnea endotracheal tubes of identical length (PVC; 30 cm length; feeling at the last experiment, irrespective of the resistance inner diameter (ID) of either 5.0 mm (“tube A”) or 4.0 mm loading and the gas mixture. (“tube B”); Rueschelit™, Teleflex Medical, Kernen, Ger- On the study day, an opaque envelope which contained many) into identical opaque PVC tubing, to prevent their the exposure schedule was drawn by the technical investi- identification from outside. The resistors had identical gators. However, the study physician and the subject were connectors on both ends that fit into adaptors to connect blinded and only the technical investigator who prepared the resistor to commercially available breathing tubes the experimental set was informed and connected tubes (Breathing tubes, Harvard Apparatus, Holliston, MA, and gas containers.

TFM Subject { Borg-Scale HELIOX (He/O2): 21

en 75%/25% 50%/50% yg Reservoir X 25%/75%

Ox vs. R V R HELIOX Medical air Helontix Vent ir lA dica Me

Fig. 1 Experimental setup [Definition of abbreviation: He helium, iment (“tube A” vs. “tube B”; see Fig. 2); Helontix Vent = mechani- HELIOX21 21% oxygen supplied in helium (79%; BOC Ltd., UK), cal ventilator which was used to mix gases (Linde Gas Therapeutics, TFM task force monitor (CNSystems, Graz, Austria)]; R1 and Lidingo, Sweden) R2 = Resistor 1 and 2, respectively, R1 was changed during the exper-

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Screening (n=50)

Inclusion (n=44)

“Pre-study” (n=44)

Randomization (n=44)

BLOCK 1 (n=11) BLOCK 2(n=11) BLOCK 3(n=11) BLOCK 4(n=11) 1. Tube A 2. Tube B 1. Tube B 2. Tube A 1. Tube A 2. Tube B 1. Tube B 2. Tube A MA MA MA MA MA MA MA MA

H25 H25 H25 H25 H75 H75 H75 H75

MA MA MA MA MA MA MA MA

H50 H50 H50 H50 H50 H50 H50 H50

MA MA MA MA MA MA MA MA

H75 H75 H75 H75 H25 H25 H25 H25

Fig. 2 Study profile. The n = 44 subjects (6 subjects excluded for Measurements with the Task Force Monitor (CNSystems) were car- upper airway infection) fulfilled all inclusion criteria were rand- ried out while subjects were breathing each gas mixture for periods omized to four different blocks (BLOCK 1–4). In each block, the of 2 min with amble time provided to allow for equilibration of the order of tested resistors as well as the sequence of mixed gases intro- respiratory tract with the tested gas mixture. The total time needed duced into the experiment were predetermined. After the crossover to carry out the experiment per subject was about 150 min (exclud- during the second run in each block, the next resistor was used again ing the initial screening examination and blood draw) (definition of with the same gases as in the first run. According to the block rand- abbreviation: MA medical air. H25, H50 and H75 mixture of a frac- omization at the end of each experiment, every subject was exposed tion of 25%, 50% and 75% helium (FiHe) in oxygen, respectively, TB to the same resistors and the same gases but in a varying order. and TA Tubes B and A)

Statistical analysis were computed for data collected over a period of 2 min for each gas–resistor combination. As a measure of variability of During a pilot study in ten healthy subjects, the tolerability systolic blood pressure (sBP), the standard deviation (SD) of of resistance loading and expected changes in dyspnea and the blood pressure was chosen and its averaged values were blood pressure had been investigated (Enneper et al. 2005). compared during resistive loading conditions breathing dif- Based on this pilot study, we estimated that significant changes ferent test gases vs. medical air (MA; Fig. 1) using a one-way, for the Borg dyspnea score and the variability of the systolic repeated-measures ANOVA with Student–Newman–Keuls blood pressure could be detected with a tube of 5 mm ID with post hoc test. For the comparison MA vs. resistive breathing HELIOX at a FiHe of 79%. Assuming a reduction in the Borg in each case, the MA-period preceding the HELIOX-exposure dyspnea score rating with HELIOX containing 50% of helium was chosen. Differences were considered significant at a cor- instead of 79%, we presumed that a fourfold increase in sample rected p-value of less than 0.05. size would be sufficient to examine our hypothesis at an alpha level of 0.05. It was expected that effects should be even more pronounced with the narrower (4.0 mm ID) tube. The Graph- Pad Prism 5 statistical software was used for data analysis (GraphPad Software, La Jolla, CA). The mean and standard deviation for Borg dyspnea scores and variability of the sBP

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Results as resistor, no significant effect on sBP-variability was detected when a Fi He of 25 and 50% were tested, i.e. only Subject characteristics the test gas with an F He of 75% reduced sBP-variability significantly. In general, the higher resistive loading condi- Out of 50 subjects screened for the study, six were excluded tion was also associated with a greater Borg dyspnea score due to upper airway infection. Table 1 summarizes the base- and larger degree of sBP-variability (Fig. 3). line characteristics of the n = 44 remaining subjects in the Assessment of Borg dyspnea scores and haemodynam- four groups as well as results of the STAI-G questionnaire ics (sBP) during the conditions “H75” at the beginning of self-assessment and “pre-study” dyspnea assessment (Borg the study (Block 1 with tube A (“TA”) in Fig. 1) vs. “H75” dyspnea score) breathing through tube A (i.e. with an inner at the end of Block 4 with tube A (“TA”) and “H25” at the diameter of 5 mm). The groups 1–4 refer to the randomi- beginning vs. the end of a block with all tubes tested did zation groups and contain 11 subjects per group. The four not reveal a statistical significant difference, i.e. the sub- groups were not statistically different with respect to the jects’ dyspnea assessment and the haemodynamic meas- reported variables (Fig. 2). urements (sBP-variability) were independent of the timing The effects of HELIOX with different FiHe on Borg during the course of the experiment as in our previous trail dyspnea score and systolic blood pressure variation are (Enneper et al. 2005). summarized in Fig. 3 during the resistive loading experi- As demonstrated in the pilot study, the mean values for ment: The patient reported Borg dyspnea score was sBP during all tested conditions and with both tubes were improved with both resistors down to a FiHe of 25%. In a not found to be statistically different (data not shown in similar fashion when the narrower tube (ID 4.0 mm) was Fig. 3) (Enneper et al. 2005). used as resistor, a mixture of helium to oxygen even at a All 44 subjects could finish the experiment without any fraction of 25% decreased the variability of systolic blood reported adverse events including no pulse-oximetry read- pressure significantly. With the larger tube (ID 5.0 mm) ings below 95%.

Fig. 3 a Borg dyspnea score ratings and b standard deviation (SD) of systolic blood pressure (sBP) are summarized during resting condition and resistive loading with two different resistors (tubes with internal diameter (ID) of 4.0 and 5.0 mm, resp.). Statistical comparison took place between the condition when the breathing circuit contained medical air vs. three different mixtures of HELIOX (with a fraction of 75, 50 and 25% in oxygen (FiHe 75%, 50% and 25%) of inspiratory helium). For completeness, the sBP-variation during unloaded breathing was also added into the figure (“breathing without resistor”)

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Discussion that even low fractions of helium can significantly lower the feeling of dyspnea, especially at higher resistance. During an acute loading experiment, it was found that Acknowledgements HELIOX with a FiHe of less than 60% can reduce patient The conduct of this investigator-initiated study was supported by Linde Gas Therapeutics (Munich/Germany) by the reported Borg dyspnea scores and sBP-variability. These provision of medical gases (Heliox, MA and Oxygen) and the Helontix- findings contradict previous views with respect to the effi- Vent™. The authors would also like to thank Dr. Ute Brauer and Dr. cacy of HELIOX with lower FiHe (Ho et al. 2002; Levy Rainer Köbrich for their advice and support with the study design; Dr. et al. 2016). HELIOX appears to be more efficient in affect- Rolf Lefering for his valuable scientific advice; and Dr. Scheffold for monitoring the study. ing outcome parameters when the diameter through which the respiratory gas has to flow is smaller, i.e. at higher load- Author contributions Conception and design: HT, SS, JS, TL, PT; ing conditions which fits well with the concept that helium is acquisition of data: HT, ABR, HD, SS, JS; statistical planning: TO, especially effective when turbulent airflow pattern is present DC; analysis and interpretation of data: HT, SW, TO; drafting of the (Hess et al. 2006; Truebel 2008), since it is not uncommon manuscript HT, TO, DC, SS, JS, TL, PT; PB final approval: all authors. for patients with upper airway obstruction (e.g. after pro- Compliance with ethical standards longed mechanical ventilation and swelling of laryngeal tissue after extubation) to also have an increased need for Conflict of interest PD Dr. Hubert Truebel organized and conducted oxygen. Thus, the addressed question if reduced fractions the trial as lead PI while working at HELIOS Klinikum Wuppertal/ of helium could effectively lower the work of breathing is of Germany until 2008. Since then he is a fulltime employee of Bayer potential clinical relevance, because one can maximize oxy- Pharma AG. Support (including gas supply and access to a HELON- gen fractions in gas mixtures applied to patients with upper TIX Vent) was received from Linde Gas Therapeutics/Germany as well as through an INSPIRA research grant by BOC/UK to cover in- airway obstruction as well as avoid using helium-containing surance and travel costs of subjects. Philip Boehme received founding gas mixtures in patients that do not need or benefit from it. from Bayer Pharma Ag. No conflicts of interest were reported by all Since helium is expensive and logistically difficult to supply, other authors. unnecessary costs can be avoided. This clinical “Proof of Concept” (phase IIa) study clearly showed that depending on the degree of airway narrowing lower FiHe still could be effective. Our experimental design has not been applied References before, but could serve as a model for future proof of concept studies in upper airway obstruction. Clinical trials with AL B (1934) Use of Helium as a new therapeutic gas. Proc Soc Exp Biol Med 32:462–464 helium should carry forward these findings in a phase IIb/III AL B (1935) The therapeutic use of helium in the treatment of asthma study design by generating evidence in a prospective manner and obstructive lesions in the larynx and trachea. Ann Intern Med addressing the issue of a “minimal effective” helium con- 9:739–765 centration in a real world scenario, i.e. in patients with acute Allan PF, Thomas KV, Ward MR, Harris AD, Naworol GA, Ward JA (2009) Feasibility study of noninvasive ventilation with helium- upper airway obstruction. 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